The major challenge in liver transplantation continues to be a need for donor organs that far exceeds the available supply. Hepatic steatosis is estimated to account for greater than 40% of discarded or non-utilized deceased donor livers. This discard rate illustrates the impact that hepatic steatosis currently has on the field of liver transplantation. Hepatic steatosis is considered to be the most important factor predicting post-transplant graft function, and the epidemic of obesity in developed societies suggests that NAFLD will increasingly complicate liver transplantation in the future. Hepatic steatosis increases the liver's susceptibility to cold ischemia and reperfusion (CIR) injury via mechanisms different from the injury observed in the lean liver. The goal of this project is to use preclinical models of liver transplant to increase our understanding of CIR injury in the steatotic liver, and to develop hepatoprotective strategies that can be tested in human liver transplantation. Given the increasing incidence of obesity, this knowledge will be necessary to both maintain the current liver utilization rate and expand the safe use of increasingly steatotic livers. Hepatic steatosis is a near universal finding in patients with the metabolic syndrome, and they have increased chronic ER stress. Although, ER stress is, in general, an adaptive response, the increased stress associated with CIR can initiate ER stress mediated cell death. Our preliminary work strongly suggests a role of ER stress in the CIR injury specific to the steatotic liver which has led us to the overarching hypothesis that acute ER stress is an important mediator of CIR associated hepatocellular injury in the steatotic liver and that attenuation of this response can decrease CIR allograft injury and improve the early functional recovery of the steatotic allograft. Organized through two specific aims, this project will test our overarching hypothesis by using a global ER stress inhibitor, taurine-conjugated ursodeoxycholic acid (TUDCA), and by also using specific inhibition of the ER stress cell death mediator, CHOP. This represents a novel approach to CIR injury and the findings of this proposal will be leveraged rapidly into clinical studies investigating the role of ER stress related allograft injury in human liver transplantation. PUBLIC HEALTH RELEVANCE: The findings of this exploratory proposal will be leveraged into clinical studies designed to exploit ER stress for hepatoprotective and predictive strategies for obese and steatotic human liver donors. This knowledge will be necessary to both maintain and expand the steatotic liver utilization rate.